Method for stabilizing flux and decreasing lag-time during iontophoresis

Abstract

An iontophoretic method for transporting compounds of interest across a body tissue is provided. The method can be used to extract analytes or deliver drugs. The method utilizes a polyelectrolyte and provides for the maintenance of a substantially constant flux across a localized region of the tissue through which transport occurs, thereby allowing a compound of interest to be transported across the tissue in a controlled and predictable manner. In addition, the presence of the polyclectrolyte reduces the lag-time of molecular transport through the body tissue.

We claim:  
     
         1 . A method of decreasing flux variability in an iontophoretic device used to transport a compound of interest through a localized region of a patient's body tissue, comprising: 
 (a) applying a current to the localized region of body tissue at a level sufficient to effect iontophoretic transport of the compound of interest therethrough;    (b) either prior to, during, or both prior to and during application of the current, applying to the localized region of body tissue an amount of at least one polyelectrolyte effective to stabilize the rate of flux of the compound of interest through the localized region of body tissue.    
     
     
         2 . The method of  claim 1  wherein the polyelectrolyte has a molecular weight of about 200 Da or greater.  
     
     
         3 . The method of  claim 2  wherein the polyelectrolyte has a molecular weight within the range of about 200-1000 Da.  
     
     
         4 . The method of  claim 2  wherein the polyelectrolyte has a molecular weight within the range of about 1000-10,000 Da.  
     
     
         5 . The method of  claim 2  wherein the polyelectrolyte has a molecular weight greater than 10,000 Da.  
     
     
         6 . The method of  claim 1  wherein the polyelectrolyte is selected from the group consisting of cationic polyelectrolytes, anionic polyelectrolytes, nonionic polyelectrolytes, amphoteric polyelectrolytes, and mixtures thereof.  
     
     
         7 . The method of  claim 6  wherein the polyelectrolyte is selected from the group consisting of cationic polyelectrolytes, anionic polyelectrolytes, and amphoteric polyelectrolytes, and comprises at least one ionic group selected from the group consisting of sulfonates, carboxylates, phosphates, and quaternary ammonium groups.  
     
     
         8 . The method of  claim 6  wherein the polyelectrolyte is selected from the group consisting of acrylamides, addition polymers, oligosaccharides and polysaccharides, polyamines, polycarboxylic acid salts, polyethylenes, polyimines, polystyrenes, and mixtures thereof.  
     
     
         9 . The method of  claim 6  wherein the polyelectrolyte is a cationic polyelectrolyte.  
     
     
         10 . The method of  claim 9  wherein the cationic polyelectrolyte comprises an ionic group selected from the group consisting of quaternary ammonium; primary, secondary, or tertiary amines charged at the reservoir solution pH; heterocyclic compounds charged at reservoir solution pH; sulfonium; and phosphonium groups.  
     
     
         11 . The method of  claim 10  wherein the cationic polyelectrolyte is selected from the group consisting of addition polymers, aminated styrenes, cholestyramine, polyimines, aminated polysaccharides, and mixtures thereof.  
     
     
         12 . The method of  claim 6  wherein the polyelectrolyte is an anionic polyelectrolyte.  
     
     
         13 . The method of  claim 12  wherein the anionic polyelectrolyte comprises an anion selected from the group consisting of carboxylate, sulfonate and phosphate groups.  
     
     
         14 . The method of  claim 13  wherein the anionic polyelectrolyte is selected from the group consisting of acrylamides, alginate, alginic acid, addition polymers, hyaluronate, oligosaccharides, pectic acid, polyacrylic acids, polysaccharides, polystyrenesulfonic acids, polyvinylphosphonic acids, and mixtures thereof.  
     
     
         15 . The method of  claim 6  wherein the polyelectrolyte is an amphoteric polyelectrolyte.  
     
     
         16 . The method of  claim 1  wherein the polyelectrolyte is selected from the group consisting of heparin and heparin derivatives, anionic and cationic liposomes, anionic and cationic micelles, polyamines, polyethylenes, polysaccharides, and mixtures thereof.  
     
     
         17 . The method of  claim 16  wherein the polysaccharide is selected from the group consisting of agaroses, celluloses, dextrans, and starch.  
     
     
         18 . The method of  claim 1  wherein the polyelectrolyte is an ion exchange material.  
     
     
         19 . The method of  claim 18  wherein the ion exchange material is selected from the group consisting of polyacrylic acids, polyacrylic sulfonic acids, polyacrylic phosphoric acids and polyacrylic glycolic acids, polyvinyl amines, polystyrenes, poly epichlorohydrin/tetraethylenetriamines, and polymers having pendent amine groups.  
     
     
         20 . The method of  claim 18  wherein the ion exchange material is a strongly acidic cation exchange resin.  
     
     
         21 . The method of  claim 18  wherein the ion exchange material is a weakly acidic cation exchange resin.  
     
     
         22 . The method of  claim 18  wherein the ion exchange material is a strongly basic anion exchange resin.  
     
     
         23 . The method of  claim 18  wherein the ion exchange material is a weakly basic anion exchange resin.  
     
     
         24 . The method of  claim 18  wherein the ion exchange material is a mixed bed resin.  
     
     
         25 . The method of  claim 1  wherein the polyelectrolyte comprises from about less than 1 wt % to greater than 90 wt % of the net reservoir weight.  
     
     
         26 . The method of  claim 25  wherein the polyelectrolyte comprises about 0.01-99 wt % of the net reservoir weight.  
     
     
         27 . The method of  claim 26  wherein the polyelectrolyte comprises about 0.25-30 wt % of the net reservoir weight.  
     
     
         28 . The method of  claim 1  wherein the iontophoretic device further comprises a membrane positioned between the polyelectrolyte and the localized region of body tissue, wherein the membrane has a pore size sufficient to prevent transport of polyclectrolyte therethrough and sufficient to permit transport of the compound of interest therethrough.  
     
     
         29 . The method of  claim 1  wherein the current is an alternating current.  
     
     
         30 . The method of  claim 29  wherein the current is applied to the localized region of the body tissue for a time period within the range of approximately 2 minutes to greater than 72 hours.  
     
     
         31 . The method of  claim 30  wherein the time period is within the range of approximately 12-72 hours.  
     
     
         32 . The method of  claim 29  wherein the current is applied at a voltage level within the range of about 1-75 V.  
     
     
         33 . The method of  claim 32  wherein the voltage level is within the range of about 1-45 V.  
     
     
         34 . The method of  claim 29  which further comprises applying a direct current prepulse prior to step (a).  
     
     
         35 . The method of  claim 29  which further comprises superimposing a direct current over the alternating current during step (a).  
     
     
         36 . The method of  claim 1  wherein the current is a direct current.  
     
     
         37 . The method of  claim 36  wherein the current is applied to the localized region of the body tissue for a time period within the range of approximately 2 minutes to greater than 72 hours.  
     
     
         38 . The method of  claim 37  wherein the time period is within the range of approximately 12-72 hours.  
     
     
         39 . The method of  claim 36  wherein the current is applied at a level within the range of about 0.01-0.5 mA/cm 2 .  
     
     
         40 . The method of  claim 39  wherein the current is applied at a level within the range of about 0.1-0.5 mA/cm 2 .  
     
     
         41 . The method of  claim 1  wherein the polyelectrolyte is applied to the localized region of body tissue prior to application of the current.  
     
     
         42 . The method of  claim 1  wherein the polyelectrolyte is applied to the localized region of body tissue during application of the current.  
     
     
         43 . The method of  claim 1  wherein the polyelectrolyte is applied to the localized region of body tissue both prior to and during application of the current.  
     
     
         44 . The method of  claim 1  wherein the body tissue is skin.  
     
     
         45 . The method of  claim 1  wherein the body tissues is ocular tissue  
     
     
         46 . The method of  claim 45  wherein the ocular tissue is selected from the group consisting of conjunctiva, sclera and cornea.  
     
     
         47 . The method of  claim 1  wherein the body tissue is mucosal tissue.  
     
     
         48 . The method of  claim 1  wherein the localized region of body tissue has an area within the range of about 0.1-100 cm 2 .  
     
     
         49 . The method of  claim 1  that provides for at least a 25% decrease in variability in the flux compared to the variability in the flux in the absence of the polyelectrolyte.  
     
     
         50 . The method of  claim 49  that provides for at least a 50% decrease in variability in the flux compared to the variability in the flux in the absence of the polyelectrolyte.  
     
     
         51 . The method of  claim 50  that provides for at least a 75% decrease in variability in the flux compared to the variability in the flux in the absence of the polyelectrolyte.  
     
     
         52 . The method of  claim 49  wherein the decreased variability is expressed as decreased intrasubject variability.  
     
     
         53 . The method of  claim 49  wherein the decreased variability is expressed as decreased intersubject variability.  
     
     
         54 . The method of  claim 1  which further provides for at least a 50% enhanced flux of the compound of interest compared to the flux in the absence of the polyelectrolyte.  
     
     
         55 . The method of  claim 54  which further provides for at least a 100% enhanced flux of the compound of interest compared to the flux in the absence of the polyelectrolyte.  
     
     
         56 . The method of  claim 55  which further provides for at least a 200% enhanced flux of the compound of interest compared to the flux in the absence of the polyelectrolyte.  
     
     
         57 . The method of  claim 1  wherein the compound of interest is a charged species.  
     
     
         58 . The method of  claim 1  wherein the compound of interest is an uncharged species.  
     
     
         59 . The method of  claim 1  wherein the compound of interest is an analyte extracted from within the patient's body, such that analyte is transported from beneath the localized region to the exterior of the body.  
     
     
         60 . The method of  claim 59  wherein the analyte is selected from the group consisting of glucose, galactose, lactic acid, pyruvic acid, and amino acids.  
     
     
         61 . The method of  claim 60  wherein the amino acid is selected from the group consisting of phenylalanine and tyrosine.  
     
     
         62 . The method of  claim 59  wherein the analyte is selected from the group consisting of diseases state markers, pharmacologically active agents, substances of abuse, electrolytes, minerals, hormones, amino acids, peptides, metal ions, nucleic acids, genes, enzymes, toxic agents, metabolites, conjugates, prodrugs, analogs and derivatives thereof.  
     
     
         63 . The method of  claim 59  wherein the analyte is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, organic acids, alcohols, fatty acids, cholesterol and cholesterol-based compounds, amino acids, zinc, iron, copper, magnesium, potassium, and metabolites, conjugates, prodrugs, analogs and derivatives thereof.  
     
     
         64 . The method of  claim 59  wherein the analyte is a pharmacologically active agent that has been administered to the patient.  
     
     
         65 . The method of  claim 64  wherein the pharmacologically active agent is selected from the group consisting of β-agonists; analeptic agents; analgesic agents; anesthetic agents; anti-angiogenic agents; anti-arthritic agents; anti-asthmatic agents; antibiotics; anticancer agents; anticholinergic agents; anticoagulant agents; anticonvulsant agents; antidepressant agents; antidiabetic agents; antidiarrheal agents; anti-emetic agents; anti-epileptic agents; antihelminthic agents; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents; anti-inflammatory agents; antimetabolites; antimigraine agents; antiparkinsonism drugs; antipruritic agents; antipsychotic agents; antipyretic agents; antispasmodic agents; antitubercular agents; anti-ulcer agents; antiviral agents; anxiolytic agents; appetite suppressants; attention deficit disorder and attention deficit hyperactivity disorder drugs; cardiovascular agents; central nervous system stimulants; cytotoxic drugs; diuretics; genetic materials; hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents; muscle relaxants; narcotic antagonists; neuroprotective agents; nicotine; nutritional agents; parasympatholytics; peptide drugs; psychostimulants; sedatives; steroids; smoking cessation agents; sympathomimetics; photoactive agents; tocolytic agents; tranquilizers; vasodilators; and active metabolites thereof.  
     
     
         66 . The method of  claim 65  wherein at least two analytes are extracted concurrently.  
     
     
         67 . The method of  claim 1  wherein the compound of interest is a pharmacologically active agent to be delivered into the patient's body.  
     
     
         68 . The method of  claim 67  wherein the pharmacologically active agent is selected from the group consisting of β-agonists; analeptic agents; analgesic agents; anesthetic agents; anti-angiogenic agents; anti-arthritic agents; anti-asthmatic agents; antibiotics; anticancer agents; anticholinergic agents; anticoagulant agents; anticonvulsant agents; antidepressant agents; antidiabetic agents; antidiarrheal agents; anti-emetic agents; anti-epileptic agents; antihelminthic agents; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents; anti-inflammatory agents; antimetabolites; antimigraine agents; antiparkinsonism drugs; antipruritic agents; antipsychotic agents; antipyretic agents; antispasmodic agents; antitubercular agents; anti-ulcer agents; antiviral agents; anxiolytic agents; appetite suppressants; attention deficit disorder and attention deficit hyperactivity disorder drugs; cardiovascular agents; central nervous system stimulants; cytotoxic drugs; diuretics; genetic materials; hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents; muscle relaxants; narcotic antagonists; neuroprotective agents; nicotine; nutritional agents; parasympatholytics; peptide drugs; psychostimulants; sedatives; steroids; smoking cessation agents; sympathomimetics; photoactive agents; tocolytic agents; tranquilizers; vasodilators; and active metabolites thereof.  
     
     
         69 . The method of  claim 67  wherein at least two pharmacologically active agents are administered simultaneously.  
     
     
         70 . A method of decreasing lag time of the iontophoretic transport of a compound of interest through a localized region of a patient's body tissue, comprising: 
 (a) applying a current to the localized region of body tissue at a level sufficient to effect iontophoretic transport of the compound of interest therethrough;    (b) either prior to, during, or both prior to and during application of the current, applying to the localized region of body tissue an amount of at least one polyelectrolyte effective to decrease the time needed to achieve steady state transport of the compound of interest through the localized region of body tissue.    
     
     
         71 . The method of  claim 70  wherein the polyelectrolyte has a molecular weight of about 200 Da or greater.  
     
     
         72 . The method of  claim 71  wherein the polyelectrolyte has a molecular weight within the range of about 200-1000 Da.  
     
     
         73 . The method of  claim 71  wherein the polyelectrolyte has a molecular weight within the range of about 1000-10,000 Da.  
     
     
         74 . The method of  claim 71  wherein the polyelectrolyte has a molecular weight greater than 10,000 Da.  
     
     
         75 . The method of  claim 70  wherein the polyclectrolyte is selected from the group consisting of cationic polyelectrolytes, anionic polyelectrolytes, nonionic polyelectrolytes, amphoteric polyelectrolytes, and mixtures thereof.  
     
     
         76 . The method of  claim 75  wherein the polyelectrolyte is selected from the group consisting of cationic polyelectrolytes, anionic polyelectrolytes, and amphoteric polyelectrolytes, and comprises at least one ionic group selected from the group consisting of sulfonates, carboxylates, phosphates, and quaternary ammonium groups.  
     
     
         77 . The method of  claim 75  wherein the polyelectrolyte is selected from the group consisting of acrylamides, addition polymers, oligosaccharides and polysaccharides, polyamines, polycarboxylic acid salts, polyethylenes, polyimines, polystyrenes, and mixtures thereof.  
     
     
         78 . The method of  claim 75  wherein the polyelectrolyte is a cationic polyclectrolyte.  
     
     
         79 . The method of  claim 78  wherein the cationic polyelectrolyte comprises an ionic group selected from the group consisting of quaternary ammonium; primary, secondary, or tertiary amines charged at the reservoir solution pH; heterocyclic compounds charged at reservoir solution pH; sulfonium; and phosphonium groups.  
     
     
         80 . The method of  claim 79  wherein the cationic polyelectrolyte is selected from the group consisting of addition polymers, aminated styrenes, cholestyramine, polyimines, aminated polysaccharides, and mixtures thereof.  
     
     
         81 . The method of  claim 75  wherein the polyelectrolyte is an anionic polyelectrolyte.  
     
     
         82 . The method of  claim 81  wherein the anionic polyelectrolyte comprises an anion selected from the group consisting of carboxylate, sulfonate and phosphate groups.  
     
     
         83 . The method of  claim 82  wherein the anionic polyelectrolyte is selected from the group consisting of acrylamides, alginate, alginic acid, addition polymers, hyaluronate, oligosaccharides, pectic acid, polyacrylic acids, polysaccharides, polystyrenesulfonic acids, polyvinylphosphonic acids, and mixtures thereof.  
     
     
         84 . The method of  claim 75  wherein the polyelectrolyte is an amphoteric polyclectrolyte.  
     
     
         85 . The method of  claim 70  wherein the polyclectrolyte is selected from the group consisting of heparin and heparin derivatives, anionic and cationic liposomes, anionic and cationic micelles, polyamines, polyethylenes, polysaccharides, and mixtures thereof.  
     
     
         86 . The method of  claim 85  wherein the polysaccharide is selected from the group consisting of agaroses, celluloses, dextrans, and starch.  
     
     
         87 . The method of  claim 70  wherein the polyelectrolyte is an ion exchange material.  
     
     
         88 . The method of  claim 87  wherein the ion exchange material is selected from the group consisting of polyacrylic acids, polyacrylic sulfonic acids, polyacrylic phosphoric acids and polyacrylic glycolic acids, polyvinyl amines, polystyrenes, poly epichlorohydrin/tetraethylenetriamines, and polymers having pendent amine groups.  
     
     
         89 . The method of  claim 87  wherein the ion exchange material is a strongly acidic cation exchange resin.  
     
     
         90 . The method of  claim 87  wherein the ion exchange material is a weakly acidic cation exchange resin.  
     
     
         91 . The method of  claim 87  wherein the ion exchange material is a strongly basic anion exchange resin.  
     
     
         92 . The method of  claim 87  wherein the ion exchange material is a weakly basic anion exchange resin.  
     
     
         93 . The method of  claim 87  wherein the ion exchange material is a mixed bed resin.  
     
     
         94 . The method of  claim 70  wherein the polyelectrolyte comprises from about less than 1 wt % to greater than 90 wt % of the net reservoir weight.  
     
     
         95 . The method of  claim 94  wherein the polyelectrolyte comprises about 0.01-99 wt % of the net reservoir weight.  
     
     
         96 . The method of  claim 95  wherein the polyelectrolyte comprises about 0.25-30 wt % of the net reservoir weight.  
     
     
         97 . The method of  claim 70  wherein the iontophoretic device further comprises a membrane positioned between the polyelectrolyte and the localized region of body tissue, wherein the membrane has a pore size sufficient to prevent transport of polyclectrolyte therethrough and sufficient to permit transport of the compound of interest therethrough.  
     
     
         98 . The method of  claim 70  wherein the current is an alternating current.  
     
     
         99 . The method of  claim 98  wherein the current is applied to the localized region of the body tissue for a time period within the range of approximately 2 minutes to greater than 72 hours.  
     
     
         100 . The method of  claim 99  wherein the time period is within the range of approximately 12-72 hours.  
     
     
         101 . The method of  claim 98  wherein the current is applied at a voltage level within the range of about 1-75 V.  
     
     
         102 . The method of  claim 101  wherein the voltage level is within the range of about 1-45 V.  
     
     
         103 . The method of  claim 98  which further comprises applying a direct current prepulse prior to step (a).  
     
     
         104 . The method of  claim 98  which further comprises superimposing a direct current over the alternating current during step (a).  
     
     
         105 . The method of  claim 70  wherein the current is a direct current.  
     
     
         106 . The method of  claim 105  wherein the current is applied to the localized region of the body tissue for a time period within the range of approximately 2 minutes to greater than 72 hours.  
     
     
         107 . The method of  claim 106  wherein the time period is within the range of approximately 12-72 hours.  
     
     
         108 . The method of  claim 105  wherein the current is applied at a level within the range of about 0.01-0.5 mA/cm 2 .  
     
     
         109 . The method of  claim 108  wherein the current is applied at a level within the range of about 0.1-0.5 mA/cm 2 .  
     
     
         110 . The method of  claim 70  wherein the polyelectrolyte is applied to the localized region of body tissue prior to application of the current.  
     
     
         111 . The method of  claim 70  wherein the polyelectrolyte is applied to the localized region of body tissue during application of the current.  
     
     
         112 . The method of  claim 70  wherein the polyelectrolyte is applied to the localized region of body tissue both prior to and during application of the current.  
     
     
         113 . The method of  claim 70  wherein the body tissue is skin.  
     
     
         114 . The method of  claim 70  wherein the body tissues is ocular tissue.  
     
     
         115 . The method of  claim 114  wherein the ocular tissue is selected from the group consisting of conjunctiva, sclera and cornea.  
     
     
         116 . The method of  claim 70  wherein the eye tissue is mucosal tissue.  
     
     
         117 . The method of  claim 70  wherein the localized region of body tissue has an area within the range of about 0.1-100 cm 2 .  
     
     
         118 . The method of  claim 70  which provides for at least a 20% reduction in lag-time compared to the lag-time in the absence of the polyelectrolyte.  
     
     
         119 . The method of  claim 118  which provides for at least a 40% reduction in lag-time compared to the lag-time in the absence of the polyelectrolyte.  
     
     
         120 . The method of  claim 119  which provides for at least a 60% reduction in lag-time compared to the lag-time in the absence of the polyelectrolyte.  
     
     
         121 . The method of  claim 70  which further provides for at least a 50% enhanced flux of the compound of interest compared to the flux in the absence of the polyelectrolyte.  
     
     
         122 . The method of  claim 121  which further provides for at least a 100% enhanced flux of the compound of interest compared to the flux in the absence of the polyelectrolyte.  
     
     
         123 . The method of  claim 122  which further provides for at least a 200% enhanced flux of the compound of interest compared to the flux in the absence of the polyelectrolyte.  
     
     
         124 . The method of  claim 70  wherein the compound of interest is a charged species.  
     
     
         125 . The method of  claim 70  wherein the compound of interest is an uncharged species.  
     
     
         126 . The method of  claim 70  wherein the compound of interest is an analyte extracted from within the patient's body, such that analyte is transported from beneath the localized region to the exterior of the body.  
     
     
         127 . The method of  claim 126  wherein the analyte is selected from the group consisting of glucose, galactose, lactic acid, pyruvic acid, and amino acids.  
     
     
         128 . The method of  claim 127  wherein the amino acid is selected from the group consisting of phenylalanine and tyrosine.  
     
     
         129 . The method of  claim 126  wherein the analyte is selected from the group consisting of diseases state markers, pharmacologically active agents, substances of abuse, electrolytes, minerals, hormones, amino acids, peptides, metal ions, nucleic acids, genes, enzymes, toxic agents, metabolites, conjugates, prodrugs, analogs and derivatives thereof.  
     
     
         130 . The method of  claim 126  wherein the analyte is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, organic acids, alcohols, fatty acids, cholesterol and cholesterol-based compounds, amino acids, zinc, iron, copper, magnesium, potassium, and metabolites, conjugates, prodrugs, analogs and derivatives thereof.  
     
     
         131 . The method of  claim 126  wherein the analyte is a pharmacologically active agent that has been administered to the patient.  
     
     
         132 . The method of  claim 131  wherein the pharmacologically active agent is selected from the group consisting of β-agonists; analeptic agents; analgesic agents; anesthetic agents; anti-angiogenic agents; anti-arthritic agents; anti-asthmatic agents; antibiotics; anticancer agents; anticholinergic agents; anticoagulant agents; anticonvulsant agents; antidepressant agents; antidiabetic agents; antidiarrheal agents; anti-emetic agents; anti-epileptic agents; antihelminthic agents; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents; anti-inflammatory agents; antimetabolites; antimigraine agents; antiparkinsonism drugs; antipruritic agents; antipsychotic agents; antipyretic agents; antispasmodic agents; antitubercular agents; anti-ulcer agents; antiviral agents; anxiolytic agents; appetite suppressants; attention deficit disorder and attention deficit hyperactivity disorder drugs; cardiovascular agents; central nervous system stimulants; cytotoxic drugs; diuretics; genetic materials; hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents; muscle relaxants; narcotic antagonists; neuroprotective agents; nicotine; nutritional agents; parasympatholytics; peptide drugs; psychostimulants; sedatives; steroids; smoking cessation agents; sympathomimetics; photoactive agents; tocolytic agents; tranquilizers; vasodilators; and active metabolites thereof.  
     
     
         133 . The method of  claim 132  wherein at least two analytes are extracted concurrently.  
     
     
         134 . The method of  claim 70  wherein the compound of interest is a pharmacologically active agent to be delivered into the patient's body.  
     
     
         135 . The method of  claim 134  wherein the pharmacologically active agent is selected from the group consisting of β-agonists; analeptic agents; analgesic agents; anesthetic agents; anti-angiogenic agents; anti-arthritic agents; anti-asthmatic agents; antibiotics; anticancer agents; anticholinergic agents; anticoagulant agents; anticonvulsant agents; antidepressant agents; antidiabetic agents; antidiarrheal agents; anti-emetic agents; anti-epileptic agents; antihelminthic agents; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents; anti-inflammatory agents; antimetabolites; antimigraine agents; antiparkinsonism drugs; antipruritic agents; antipsychotic agents; antipyretic agents; antispasmodic agents; antitubercular agents; anti-ulcer agents; antiviral agents; anxiolytic agents; appetite suppressants; attention deficit disorder and attention deficit hyperactivity disorder drugs; cardiovascular agents; central nervous system stimulants; cytotoxic drugs; diuretics; genetic materials; hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents; muscle relaxants; narcotic antagonists; neuroprotective agents; nicotine; nutritional agents; parasympatholytics; peptide drugs; psychostimulants; sedatives; steroids; smoking cessation agents; sympathomimetics; photoactive agents; tocolytic agents; tranquilizers; vasodilators; and active metabolites thereof.  
     
     
         136 . The method of  claim 134  wherein at least two pharmacologically active agents are administered simultaneously.